Secrets of Aging

Leonard Guarente, who explores how to slow the aging process, once had a student who thought he’d try doing it the hard way.

The student, who was taking a summer course Guarente taught on Cape Cod, had cut his daily calorie intake by more than a third. His rationale? Animal studies have shown that cutting food intake slows aging. (“In some studies,” notes Guarente, an MIT professor of biology, “calorie restriction has boosted life spans by 100 percent.”)

But it’s a tough way to live, as Guarente’s description makes clear: “This student was very thin,” says the faculty member, “he was cold a lot” – because he lacked the protective layer of fat most of us carry around – “and he didn’t seem to have much fun.”

Guarente adds that when people ask him about hyper-dieting, “I tell them not to. It’s too difficult to maintain that kind of regimen, and there’s no study showing that it works in humans.”

On the other hand, studies in many types of organisms suggest that something about cutting calories slows aging. “What everybody wants to know,” says Guarente, “is whether there’s a common mechanism at work in all these species.”

The faculty member is among the leaders of efforts to find out. And his work points to a mind-boggling possibility: that aging could turn out to be largely traceable to a single gene. “When I started looking at this problem,” he notes, “there was a feeling that aging is due to a thousand things going wrong, so there would be no way to tinker with any one thing and make a difference.”

But Guarente says that now the idea of slowing the aging process – a dream that has probably absorbed the human psyche as long as thought itself has existed – is no longer unthinkable.

Not focused on MIT

Guarente’s route to leadership in research on aging had a lot of twists and turns. Raised in the gritty Boston-area community of Revere, he initially didn’t give a thought to attending MIT. As a student at the Jesuit-run Boston College High School, though, he learned the Institute might be in reach for him.

“I knew that it was a very good school,” he says, “and I found out it was potentially affordable to people of limited means.”

So, Guarente applied, was admitted – and the gathering momentum behind the biological revolution triggered by the discovery of DNA’s structure soon gave him an intellectual focus.

His concept of biology, he says, had been that it’s mostly about classifying different species. “That seemed extremely boring. So when I found out there was this new thing called molecular biology, I really became curious about it.”

His curiosity was enough of a motivator to help him blaze a glittering academic trail at MIT, and later Harvard. That in turn led to an appointment to the MIT faculty.

Guarente spent roughly a decade exploring basic questions about how genes work. Then, he decided to make a risky career move: “I’d gotten tenure,” he explains, “and so I tried to think about some of the problems in biology that were poorly understood. Aging seemed like one that was worth a shot.”
Key discoveries

Guarente knew many biologists thought the aging process was hugely complicated, but he had a hunch they were wrong. “The one clue we did have,” he says, “was the efficacy of calorie restriction.”

He started probing what it is about cutting calories that slows aging. He worked with yeast – a fungus that’s best known for its role in fermenting beer and inflating dough, but that in fact shares many genes with humans and is also an easy organism to study.

At first, progress was glacial. But starting in the mid-90s, the pace picked up markedly. First, Guarente showed that what slows aging in yeast cells is that the activation of some genes is suppressed. Then, his group demonstrated that a specific gene, dubbed SIR2, seems to be the key to this “gene silencing” phenomenon. Finally, the researchers found an intriguing connection between SIR2 and the effects of hyper-dieting.

The link is a kind of cellular version of Superman. In its Clark Kent role, this agent – known by the tongue-twisting name of nicotinamide-adenine dinucleotide (NAD) – helps an organism’s cells reap the benefits of food in the system. In nutriment-deprived cells, though, this Superman agent is freed up to focus on another role: boosting the SIR2 gene’s activity.

“The idea,” says Guarente, “is that the level of NAD available in cells dictates the strength of their SIR2 activity, which then dictates the pace of aging. That’s the grand hypothesis, and we’re currently trying to test it in worms and in mice.”

What might all this mean for people? Provocative findings from Guarente’s and others’ labs suggest the NAD-SIR2 link may be common in the animal kingdom. Studies also show that SIR2’s protein product acts as an enzyme in other organisms besides yeast. Such findings in turn hint that it may soon be possible to think about strategies for slowing the aging process.

Guarente notes that the effect of any such strategy would probably not be to prolong life, but rather to stave off some effects of aging, like the nagging ailments, loss of strength, and other problems that afflict most seniors. He also emphasizes that not enough is known yet to predict the idea’s feasibility.

Still, he believes that some means for slowing the aging process may well emerge over the next decade or so. “What we’d need to do is to trick someone’s system into thinking that it’s calorie-restricted even when it’s not,” explains Guarente, “and this might not be that difficult.”